The proposed studies will examine the function of the endothelium in biological and synthetic vascular grafts. In vitro techniques used to study endothelium-dependent responses in arteries and veins will be used to determine the functional state of the intima of autografts, allografts and of the neointima of synthetic vascular &rafts. A key question is whether the endothelium of veins implanted into the arterial circulation (vein grafts) produce and release factors in addition to metabolites of arachidonic acid which can modulate the tone of the underlying smooth muscle and act synergistically with prostacyclin to inhibit platelet aggregation. These experiments will identify the presence of chemical substances which could limit or promote thrombus formation, an important factor in limiting patency in vascular grafts. Other studies are designed to examine differences in the production and release of endothelium-derived factors in vein grafts implanted in the reverse and nonreverse (in situ) position and between vein grafts exposed chronically to low and high blood flows. These studies will identify physical factors which could alter endothelial function and therefore the patency of the grafts. It will be determined whether changes in responses of the vein grafts result from altered function of the endothelium or of the smooth muscle. By using selective inhibitors of receptors and enzymatic pathways, the mechanism of action of endothelium-derived factors will be determined. Similar studies will be performed on cryopreserved veins before and after implantation into the arterial circulation. Changes in endothelial function will be correlated with platelet adhesion to the cryopreserved allografts sequentially following implantation. The ability of the neointima of synthetic grafts to release endothelium-derived substance other than prostacyclin will be determined. The effectiveness of these substances to inhibit platelet aggregation will be compared between grafts seeded with endothelial cells of venous or arterial origin. It is anticipated that these experiments will identify particular deficits in the function of endothelial cells of vascular grafts which could lead to selected therapy to improve graft patency. They will provide new information crucial to understanding mechanisms associated with thrombus formation in and occlusion of vascular grafts.